The program is broadly oriented to the study of subcellular or, biochemical and ultra-structural effects of heavy metals. Objectives to be pursued are the manner in which metals are metabolized in cells including harmful effects of small doses. Adaptive mechanisms and their cost to the overall metabolism of the cell is also considered. Particular study to date has concerned subcellular effects of lead. Intranuclear inclusion bodies occurring in liver and renal cells in lead poisoning have been found to be composed of lead-protein complexes. The protein is an acidic protein, similar to other nuclear acidic proteins, but more precise study of its biochemical nature and source as well as its role in adaptation to lead is under study. Similar protein complexes with other metals (bismuth) are also under study. Factors synergistic or antagonistic to the effects of lead are being investigated in terms of their effect on the lowest dosage of lead which will produce a measurable effect in the rat. Neuropathologic effects of lead including the cellular ultrastructure and central nervous system distribution of lead is being observed in neonatal rats and puppies. Studies on the reproductive effects of lead have shown that lead produces both a paternal as well as maternal effect, presumably at the level of the gamete. Ova of lead-poisoned female rats are abnormal histologically. Lead also impairs shell-formation in chicken eggs and analysis of distribution of lead within the chicken egg shows the largest amount of lead to be located in the yolk protein. The shell gland mucosa of ovulating lead-toxic hens was found to contain significantly less carbonic anhydrous than similar mucosa from control hens. More sensitive methods for measuring metals are under study using gas-liquid chromatography, mass spectroscopy and x-ray fluorescence.